In vitro investigation of BK-218, a new oral and parenteral cephalosporin

Abstract

The antibacterial activity of BK-218 was similar to that of cefamandole when it was tested against several laboratory strains. The inhibiting effect of BK-218 was greater than that of cephalexin and cefoxitin on penicillin-binding proteins of Escherichia col HB101. This result was in close correlation with the relative inhibition of radiolabeled glucosamine incorporation (greatest with BK-218) and with the lytic effect (most intensive with BK-218). BK-218 proved to be a good inhibitor for all five of the ,-lactamases that were investigated, although two enzymes (Enterobacter cloacae P99 and Pseudomonas aeruginosa Cilote) hydrolyzed it to some extent.Cephalexin (4), cefadroxil (7), cefaclor (4,21), cefroxadine (34), and cefatrizine (22) (Fig. 1.), is a new oral cephalosporin.It is well-known that beta-lactam antibiotics first bind to their targets, the so-called penicillin-binding proteins (PBPs). The inhibition of these enzymes suspends peptidoglycan synthesis, and as a consequence the autolytic enzymes are triggered with a mechanism whose details are not completely understood (16).The purpose of this study was to report the results of preliminary investigations concerning the in vitro activity of BK-218 against a limited number of gram-positive and gramnegative bacteria. The MICs of BK-218 were compared with those of other parenteral (cefuroxime, cefamandole, and cefoxitin) and oral (cephalexin) antibiotics.The in vitro effect on the targets was measured by (i) affinity to PBPs, (ii) incorporation of labeled glucosamine into the cell wall of Escherichia coli, and (iii) release of labeled glucosamine-containing fragments from prelabeled cell wall of E. coli to assess the lysis capability of BK-218.

Antibacterial activity of the investigational oral and parenteral cephalosporin BK-218

“…The strains were distributed as follows: 208 Enterobacteriaceae, 10 Acinetobacter anitratus, 31 Haemophilus influenzae (11 beta-lactamase positive, 10 beta-lactamase negative ampicillin-susceptible, and 10 beta-lactamase negative ampicillin resistant), 20 Moraxella catarrhalis (10 betalactamase positive, 10 beta-lactamase negative), 34 Neisseria gonorrhoeae, 16 (Table 3). Cefuroxime, Cefaclor, and cefixime were also inactive against these organisms, while ciprofloxacin was most ac- (2) 81, > 161 Aeromonas hydrophila (2) > 162 Citrobacter amalonatica (2) 81, > 161 EnterobactersakazaMi (2) 0.51, > 161 Enterobacter taylorae (1) > 161 Flavobacterium spp. (2) > 16z Hafnia afvei (2) > 162 Klebsiella ozaenae (2) 0.121, 0.251 Pseudomonas cepacia (2) > 162 Pseudomonasfluoreseens (3) > 163 Sahnonella typhi (1) 0.121 Serratia liquefaciens (1) > 161 *The subscript is the number of isolate occurrences at each MIC result.…”

“…BK-218 was also moderately stable to the hydrolysis of several clinical prevalent beta-lac. tamases investigated (1). Like BK-218, several other investigational orally administered cephalosporins have been described that provide increased potency against gram-negative pathogens and a greater beta-lactamase stability (3).…”

“…BK-218 is a new orally and parenterally administered cephalosporin (1). BK-218 has a chlorine attached to the 7-position side chain.…”

“…The fluorinated quinolones and naphthyridines have become significant antimicrobial agents in the last ten years (1). Numerous modifications of these structures have produced several widespectrum compounds of clinical importance including ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin (1, 2).…”

“…In a previous study (1), BK-218 was found to be active again s t m any st ra i n s o f En terobacteriaceae, Staphylococci tested were taken from a stock culture collection. BK-218 was also moderately stable to the hydrolysis of several clinical prevalent beta-lac.…”